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The idea of shrinking amyloid plaques by drawing Ab out of the brain and into the circulation, where it can be destroyed, lately has gained some acceptance. Just recently, circulating antibodies were shown to soak up brain Ab in mouse models of Alzheimer's (see ARF news story). An alternative would be to use a small molecule drug that would disrupt amyloid by targeting one of its constituents, ideally one that can be easily manipulated. Enter SAP, or serum amyloid P component.

SAP is a proteolytically inert glycoprotein that binds to all known amyloid fibrils and is thought to protect them from degradation. If SAP could be taken out of the equation, the fibrils might be more easily removed by the body's own clearance mechanisms. In tomorrow's Nature, Mark Pepys, Royal Free and University College Medical School, London, together with colleagues elsewhere, report on the development of a small-molecule drug, which dimerizes SAP. This prevents SAP from binding to amyloid and in this way exposes the amyloid to proteases. The drug, CPHPC, was found by its ability to block SAP binding to immobilized Ab fibrils. The palindromic molecule, its two identical ends separated by an alkyl chain, can cross-link two SAP molecules.

Pepys et al showed by x-ray crystallography that five molecules of CPHPC act like the nuts on a car wheel, binding two donut-shaped pentamers of SAP together to form a decamer. The drug rapidly cleared human SAP from transgenic mice expressing it. Within five days, mouse SAP was completely eliminated from amyloid deposits induced in normal animals.

Results in humans were similar. Intravenous infusion of CPHPC rapidly cleared SAP from the serum, and in patients with systemic amyloidosis (of monoclonal immunoglobulin light chain) whole body imaging showed that SAP was depleted from amyloid in the organs. The human study was not designed to assess whether symptoms improved in the patients, but Pepys said that some of them were in the end-stages of disease and remained stable during the course of treatment.

Whether CPHPC can shrink amyloid deposits remains to be seen, Leslie Iversen of King's College, London, points out in an accompanying News and Views. It is encouraging, however, that the drug is rapidly cleared from the body and has little or no side-effects, most likely because it is not metabolized, said Pepys, who is about to start a small clinical trial of the drug for Alzheimer's disease.—Tom Fagan

Comments

Comments on News and Primary Papers

This is a beautiful paper that follows a large body of excellent work from these investigators. However, no data is presented as to how the disruption of the interaction between SAP and amyloid fibrils by their drug candidate affects the fate of the amyloid itself. This paper is focused exclusively on the clearance of SAP from the deposits. The authors state that they hope that the clearance of SAP will "reduce the stability of amyloid deposits and promote their regression". This is certainly a reasonable hypothesis, given that other studies have shown amyloid deposits can be cleared and that the SAP knockout mouse showed retarded and reduced disease.

However, it is very important to note that the systemic amyloidoses discussed in this paper seem to be caused by the amyloid fibrils themselves, whereas the neurodegenerative amyloidoses, including PD and AD, seem to be caused by a fibril precursor, or protofibril. In the latter cases, a molecule that promotes fibril accumulation (and protofibril depletion) could actually slow disease progression by removing the toxic species. Ron Kopito's aggresome model emphasizes that there may be evolved mechanisms to detoxify protein aggregates in the cytoplasm (Kopito, 2000).

Thus, the strategy discussed here could be very useful for systemic amyloid diseases, but is less likely to be useful for neurodegenerative disease. In fact, it may not be wise to interfere with such an interaction in the latter diseases.

In the paper, serum amyloid P is depleted from plasma with a new drug. While SAP has nothing to do with Abeta (it binds to other amyloids in peripheral amyloidosis), it raises the possibility as to whether one can deplete an Aβ binding protein such as apoE or others as a treatment for AD. Whether one would need to do this in the brain vs. plasma vs. both is not clear.